The process of tooth eruption is dependent on numerous events, cells and factors, many of which have been initially identified, but are as of yet poorly defined. Existing evidence suggests that factors secreted by cells within the dental follicle region promote both the recruitment of mononuclear cells, and their differentiation into osteoclasts with subsequent alveolar bone resorption as required for tooth eruption. Paralleling tooth eruption is the development of a functional periodontal ligament (PDL). Maintenance of this non-mineralized ligament and post-functional eruption is also thought to be dependent on factors secreted by cells within the follicle/PDL region. Preliminary data indicate that dental follicle cells have receptors for parathyroid hormone-related protein (PTHrP) and observations that PTHrP knock-out mice have defective tooth eruption lead to the hypothesis that follicle cells are required for tooth eruption via their PTHrP-mediated stimulation of osteoclastic activity and inhibition of mineralization. Three specific aims will test this hypothesis using in vitro and in vivo models. The first will define the actions of PTHrP at the PTH type 1 receptor (PTH-1R) on cells in the microenvironment of the developing tooth that are considered to promote osteoclast differentiation and activation. The second aim will define the actions of PTHrP at the PTH-1 receptor on cells in the microenvironment of the developing tooth that are considered to inhibit mineralization and thus maintain a functional PDL and prevent ankylosis. Lastly, the third aim will identify and characterize the transcriptional mediators of osteoclast activators and mineralization inhibitors operative in facilitating tooth eruption. By identifying the mediators and signaling molecules of PTHrP during tooth eruption, these studies will provide critical information required for defining the molecular mechanisms operative during tooth eruption. This valuable information will facilitate the design of therapeutic and preventive strategies to address conditions of altered tooth development and eruption that contribute to malocclusion and compromised oral health and function. Furthermore, these studies will enhance our basic knowledge as to the role of PTHrP and PTH-1R interactions in controlling mineralized tissue homeostasis.